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Publication Abstract from PubMed

Choline kinase alpha (ChoKalpha) is an enzyme that is upregulated in many types of cancer and has been shown to be tumorigenic. As such, it makes a promising target for inhibiting tumor growth. Though there have been several inhibitors synthesized for ChoKalpha, not all of them demonstrate the same efficacy in vivo, though the reasons behind this difference in potency are not clear. One particular inhibitor, designated TCD-717, has recently completed phase I clinical trials. Cell culture and in vitro studies support the powerful inhibitory effect TCD-717 has on ChoKalpha, but an examination of the inhibitor's interaction with the ChoKalpha enzyme has been missing prior to this work. Here we detail the 2.35 A structure of ChoKalpha in complex with TCD-717. Examination of this structure in conjunction with kinetic assays reveals that TCD-717 does not bind directly in the choline pocket as do previously characterized ChoKalpha inhibitors, but rather in a proximal but novel location near the surface of the enzyme. The unique binding site identified for TCD-717 lends insight for the future design of more potent in vivo inhibitors for ChoKalpha.

Identification of a Unique Inhibitor-Binding Site on Choline Kinase alpha.,Kall SL, Delikatny EJ, Lavie A Biochemistry. 2018 Feb 8. doi: 10.1021/acs.biochem.7b01257. PMID:29389115^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.